There is currently a great interest in developing pharmaceuticals based on the growing understanding of the structure and function of the major histocompatibility complex (MHC) antigens. These cell surface glycoproteins are known to play an important role in antigen presentation and in eliciting a variety of T cell responses to antigens.
T cells, unlike B cells, do not directly recognize antigens. Instead, an accessory cell must first process the antigen and present it in association with an MHC molecule in order to elicit an immunological response. The major function of MHC glycoproteins appears to be the binding and presentation of processed antigen in the form of short antigenic peptides.
In addition to binding foreign or "non-self" antigenic peptides, MHC molecules can also bind "self" peptides. If T lymphocytes then respond to cells presenting "self" or autoantigenic peptides, a condition of autoimmunity results. Over 30 autoimmune diseases are presently known, including myasthenia gravis (MG), multiple sclerosis (MS), systemic lupus erythematisus (SLE), rheumatoid arthritis (RA), insulin-dependent diabetes mellitus (IDDM), etc. Characteristic of these diseases is an attack by the immune system on the tissues of the victim. In non-diseased individuals, such attack does not occur because the immune system recognizes these tissues as "self". Autoimmunity results when the ability to recognize certain autoantigens as "self" is lacking.
Insulin-dependent diabetes mellitus (IDDM) is a disease resulting from the autoimmune destruction of the insulin-producing .beta.-cells of the pancreas. Studies directed at identifying the autoantigen(s) responsible for .beta.-cell destruction have identified several candidates, including insulin (Palmer et al., Science 222: 1337-1339, 1983), a poorly characterized islet cell antigen (Bottazzo et al, Lancet ii: 1279-1283, 1974) and a 64 kDa antigen that has been shown to be glutamic acid decarboxylase (Baekkeskov et al., Nature 298: 167-169 (1982); Baekkeskov et al., Nature 347: 151-156, 1990). Antibodies to glutamic acid decarboxylase (hereinafter referred to as "GAD") have been found to be present in patients prior to clinical manifestation of IDDM (Baekkeskov et al, J. Clin. Invest. 79: 926-934, 1987).
GAD catalyzes the rate-limiting step in the synthesis of c-aminobutyric acid (GABA), a major inhibitory neurotransmitter of the mammalian central nervous system. Little is known with certainty regarding the regulation of GAD activity or the expression of GAD genes. Despite its wide distribution in the brain, GAD protein is present in very small quantities and is very difficult to purify to homogeneity. GAD has multiple isoforms encoded by different genes. These multiple forms of the enzyme differ in molecular weight, kinetic properties, sequence (when known), and hydrophobic properties. For example, the presence of three different forms of GAD in porcine brain has been reported (Spink et al., J. Neurochem. 40: 1113-1119, 1983), as well as rour forms in rat brain (Spink et al., Brain Res. 421: 235-244, 1987). A mouse brain GAD (Huang et al., Proc. Natl. Acad. Sci. USA 87: 8491-8495, 1990) and a GAD clone isolated from feline brain (Kobayashi et al., J. Neurosci. 7: 2768-2772, 1987) have also been reported. At least two isomers of GAD have been reported in human brain (Chang and Gottlieb, J. Neurosci. 8: 2123-2130, 1988). A human pancreatic islet cell GAD has recently been characterized by molecular cloning (Lernmark et al., U.S. patent application Ser. No. 07/702,162; PCT publication WO 92/20811). This form of GAD is identical to one subsequently identified human brain isoform (Bu et al., Proc. Natl. Acad. Sci. USA 89: 2115-2119, 1992). A second GAD isoform identified in human brain is not present in human islets (Karlsen et al., Diabetes 41: 1355-1359, 1992).
Evidence suggests that GAD is the primary autoantigen responsible for initiating the .beta. cell assault leading to diabetes both in humans and in animal models. Three peptides derived from mouse and human GAD65, peptide #17 sequence 246-266, peptide #34 sequence 509-528 and peptide #35 sequence 524-543, have been implicated as candidates for the autoantigen by their ability to induce a T cell response in mice (Kaufman et al., Nature 366: 69-71).
Current treatment for autoimmune disease and related conditions consists primarily of treating the symptoms, but not intervening in the etiology of the disease. Broad spectrum chemotherapeutic agents are typically employed, which agents are often associated with numerous undesirable side effects. Therefore, there is a need for compounds capable of selectively suppressing autoimmune responses by blocking MHC binding, thereby providing a safer, more effective treatment. In addition, such selective immunosuppressive compounds are needed in the treatment of non-autoimmune diseases, such as graft versus host disease (GVHD) or various allergic response. For instance, chronic GVHD patients frequently present conditions and symptoms similar to certain autoimmune diseases.
The inadequate treatments presently available illustrate the urgent need to identify new agents that block MHC-restricted immune responses, but avoid undesirable side effects such as nonspecific suppression of an individual's overall immune response. A desirable approach to treating autoimmune diseases and other pathological conditions mediated by MHC is to use antagonists to block binding to the T cell receptor. The present invention fulfills such needs, and provides related advantages.